Nakashima T, Taurog A, Riesco G
Endocrinology. 1978 Dec;103(6):2187-97. doi: 10.1210/endo-103-6-2187.
Experiments were performed with rats to test the physiological significance of a previously proposed mechanism of action of thioureylene antithyroid drugs, which had been derived from results obtained with a model system containing purified thyroid peroxidase. Two features of the previously proposed scheme were tested:1) the effects of drug dosage and 2) the effects of iodine deficiency. In the dosage experiments, rats were injected with graded doses of [35S]PTU (0.18-59 mumol or [35S]mmi (0.16-18 mumol). Thyroid glands were removed 1 and 6--8 h later and 35S distribution in the homogenates was determined by paper chromatography. Serum samples were also analyzed by the same procedure. From the measured 35S activity in the various components and from the known specific activity of the injected drugs, it was possible to calculate thyroidal concentrations of unchanged drug and drug metabolites. At low doses, thyroidal concentrations of unchanged 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MM) significantly exceeded their concentrations in serum, as reported by previous investigators. A major new finding in the present investigation was the observation that intrathyroidal metabolism of PTU and MMI is greatly affected by dosage. Marked inhibition of intrathyroidal drug metabolism was observed at 6-8 when the dosage was increased from 5.9 to 18 mumol for [35S]PTU and from 0.88 to 2.2 mumol for [35S]MMI (per 200 g rat). These findings demonstrate that with increasing dosage, PTU and MMI inhibit their own intrathyroidal metabolism. These dosage effects are similar to results previously reported for in vitro oxidation of PTU and MMI by the thyroid peroxidase system, and they offer support for the physiological significance of the previously proposed scheme. Further evidence for the physiological validity of this scheme was obtained in the experiments with iodine-deficient rats. As predicted from the in vitro findings, intrathyroidal metabolism of [35S]PTU and [35S]MMI was markedly reduced in rats on low iodine diet.
用大鼠进行实验，以测试先前提出的硫脲类抗甲状腺药物作用机制的生理意义，该机制源自含有纯化甲状腺过氧化物酶的模型系统所获得的结果。对先前提出的方案的两个特征进行了测试：1）药物剂量的影响和2）碘缺乏的影响。在剂量实验中，给大鼠注射分级剂量的[35S]丙硫氧嘧啶（PTU）（0.18 - 59 μmol）或[35S]甲巯咪唑（MMI）（0.16 - 18 μmol）。1小时以及6 - 8小时后取出甲状腺，通过纸色谱法测定匀浆中35S的分布。血清样本也采用相同程序进行分析。根据在各种成分中测得的35S活性以及注射药物的已知比活性，可以计算出甲状腺中未变化药物和药物代谢物的浓度。如先前研究者所报道，在低剂量时，甲状腺中未变化的6 - 丙基 - 2 - 硫氧嘧啶（PTU）和1 - 甲基 - 2 - 巯基咪唑（MM）的浓度显著超过其在血清中的浓度。本研究的一个主要新发现是观察到PTU和MMI的甲状腺内代谢受剂量的极大影响。当[35S]PTU的剂量从5.9 μmol增加到18 μmol以及[35S]MMI的剂量从0.88 μmol增加到2.2 μmol（每200 g大鼠）时，在6 - 8小时观察到甲状腺内药物代谢受到明显抑制。这些发现表明，随着剂量增加，PTU和MMI会抑制它们自身的甲状腺内代谢。这些剂量效应与先前报道的甲状腺过氧化物酶系统对PTU和MMI的体外氧化结果相似，并且为先前提出方案的生理意义提供了支持。在缺碘大鼠的实验中获得了该方案生理有效性的进一步证据。正如从体外研究结果所预测的那样，低碘饮食大鼠中[35S]PTU和[35S]MMI的甲状腺内代谢明显减少。
